PET imaging of α7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans

Hillmer, Ansel T.; Li, Songye; Zheng, Ming-Qiang; Scheunemann, Matthias; Lin, Shu-fei; Nabulsi, Nabeel; Holden, Daniel; Pracitto, Richard; Labaree, David; Ropchan, Jim; Teodoro, Rodrigo; Deuther‐Conrad, Winnie; Esterlis, Irina; Cosgrove, Kelly P.; Brust, Peter; Carson, Richard E.; Huang, Yiyun

doi:10.1007/s00259-017-3621-8

Cited by 51 publications

(39 citation statements)

References 38 publications

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“…Due to the limited number of animals in this study, this observation merits further investigations. Our finding is however supported by PET studies in non-human primates with [ 18 F]ASEM and [ 18 F]DBT-10, where V T /f P was shown to be a more stable outcome measure than V T [44,45]. This has also been shown for radiotracers binding to other neurotransmitter receptors [75].…”

Section: Discussionsupporting

confidence: 78%

“…This phenomenon was most pronounced in the thalamus and least pronounced in the white matter and is evident from the TACs (Figure 4A), where the ratio between e.g., thalamus and cerebellum was lower at 240 min than at 90 min. This finding is in contrast with the non-human primate and human data, where V T was underestimated when reducing the PET data from 180 to 60 min [44]. Given that ASEM is an antagonist, it is unlikely that internalization of the receptor-ligand complex is an explanation for the decrease in V T .…”

Section: Discussioncontrasting

confidence: 71%

“…Although the injected doses of ASEM varied in the two baseline animals, we only found a 5% difference in the calculated V T /f P , which suggest that the studies were conducted at tracer doses. The injected doses in this study (0.007-0.085 ug/kg) are higher than the doses used in the non-human primate evaluation of [ 18 F]ASEM, where injected doses ranged from 0.009 to 0.056 µg/kg [44]. Further studies are needed to identify the mass dose limit of unlabelled ASEM.…”

Section: Discussionmentioning

confidence: 81%

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In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [125I]Iodo-ASEM and [18F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors

Donat

Hansen

et al. 2020

Molecules

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The α7 nicotinic acetylcholine receptor (α7 nAChR) is involved in several cognitive and physiologic processes; its expression levels and patterns change in neurologic and psychiatric diseases, such as schizophrenia and Alzheimer’s disease, which makes it a relevant drug target. Development of selective radioligands is important for defining binding properties and occupancy of novel molecules targeting the receptor. We tested the in vitro binding properties of [125I]Iodo-ASEM [(3-(1,4-diazabycyclo[3.2.2]nonan-4-yl)-6-(125I-iododibenzo[b,d]thiopentene 5,5-dioxide)] in the mouse, rat and pig brain using autoradiography. The in vivo binding properties of [18F]ASEM were investigated using positron emission tomography (PET) in the pig brain. [125I]Iodo-ASEM showed specific and displaceable high affinity (~1 nM) binding in mouse, rat, and pig brain. Binding pattern overlapped with [125I]α-bungarotoxin, specific binding was absent in α7 nAChR gene-deficient mice and binding was blocked by a range of α7 nAChR orthosteric modulators in an affinity-dependent order in the pig brain. Interestingly, relative to the wild-type, binding in β2 nAChR gene-deficient mice was lower for [125I]Iodo-ASEM (58% ± 2.7%) than [125I]α-bungarotoxin (23% ± 0.2%), potentially indicating different binding properties to heteromeric α7β2 nAChR. [18F]ASEM PET in the pig showed high brain uptake and reversible tracer kinetics with a similar spatial distribution as previously reported for α7 nAChR. Blocking with SSR-180,711 resulted in a significant decrease in [18F]ASEM binding. Our findings indicate that [125I]Iodo-ASEM allows sensitive and selective imaging of α7 nAChR in vitro, with better signal-to-noise ratio than previous tracers. Preliminary data of [18F]ASEM in the pig brain demonstrated principal suitable kinetic properties for in vivo quantification of α7 nAChR, comparable to previously published data.

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Section: Discussionsupporting

confidence: 78%

Section: Discussioncontrasting

confidence: 71%

Section: Discussionmentioning

confidence: 81%

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In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [125I]Iodo-ASEM and [18F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors

Donat

Hansen

et al. 2020

Molecules

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“…18 F-FEOBV, 18 F-VAT, and 18 F-ASEM all show good peak brain activity, heterogeneous distribution in line with target distribution, and moderate to fast kinetics in most brain regions [65,73]. The exception is the slow kinetics of 18 F-FEOBV in basal ganglia structures requiring long scan durations or delayed scanning protocols for quantification in this region [65].…”

Section: Pharmacokinetic Properties Of Cholinergic Tracersmentioning

confidence: 87%

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

McCluskey

Plisson

Rabiner

et al. 2019

Eur J Nucl Med Mol Imaging

102

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Purpose A limit on developing new treatments for a number of central nervous system (CNS) disorders has been the inadequate understanding of the in vivo pathophysiology underlying neurological and psychiatric disorders and the lack of in vivo tools to determine brain penetrance, target engagement, and relevant molecular activity of novel drugs. Molecular neuroimaging provides the tools to address this. This article aims to provide a state-of-the-art review of new PET tracers for CNS targets, focusing on developments in the last 5 years for targets recently available for inhuman imaging. Methods We provide an overview of the criteria used to evaluate PET tracers. We then used the National Institute of Mental Health Research Priorities list to identify the key CNS targets. We conducted a PubMed search (search period 1st of January 2013 to 31st of December 2018), which yielded 40 new PET tracers across 16 CNS targets which met our selectivity criteria. For each tracer, we summarised the evidence of its properties and potential for use in studies of CNS pathophysiology and drug evaluation, including its target selectivity and affinity, inter and intra-subject variability, and pharmacokinetic parameters. We also consider its potential limitations and missing characterisation data, but not specific applications in drug development. Where multiple tracers were present for a target, we provide a comparison of their properties. Results and conclusions Our review shows that multiple new tracers have been developed for proteinopathy targets, particularly tau, as well as the purinoceptor P2X7, phosphodiesterase enzyme PDE10A, and synaptic vesicle glycoprotein 2A (SV2A), amongst others. Some of the most promising of these include 18 F-MK-6240 for tau imaging, 11 C-UCB-J for imaging SV2A, 11 C-CURB and 11 C-MK-3168 for characterisation of fatty acid amide hydrolase, 18 F-FIMX for metabotropic glutamate receptor 1, and 18 F-MNI-444 for imaging adenosine 2A. Our review also identifies recurrent issues within the field. Many of the tracers discussed lack in vivo blocking data, reducing confidence in selectivity. Additionally, late-stage identification of substantial off-target sites for multiple tracers highlights incomplete preclinical characterisation prior to translation, as well as human disease state studies carried out without confirmation of test-retest reproducibility.

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“…The brain uptake of 18 F-DBT-10 was inhibited by the administration of ASEM, in a dose-dependent manner (Hillmer et al 2016b). Hillmer et al directly compared the in vivo kinetic properties of 18 F-ASEM and 18 F-DBT-10 in identical rhesus monkeys and concluded that the two radiotracers were highly similar (Hillmer et al 2017).…”

Section: Imaging Probes For the α7 Subtypementioning

confidence: 99%

Nicotinic Acetylcholine Receptor Signaling in Neuroprotection

Akaike

Shimohama

Misu

2018

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show abstract

PET imaging of α7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans

Cited by 51 publications

References 38 publications

In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [125I]Iodo-ASEM and [18F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors

In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [125I]Iodo-ASEM and [18F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

Nicotinic Acetylcholine Receptor Signaling in Neuroprotection

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